On December 1, 2018 X4 Pharmaceuticals, a clinical stage biotechnology company developing novel CXCR4 allosteric antagonist drugs to improve immune cell trafficking to treat rare diseases and cancer, reported the presentation of additional Phase 2 clinical data demonstrating a positive safety profile and clinical activity of X4P-001 in patients with WHIM syndrome, a rare primary immunodeficiency disease (Press release, X4 Pharmaceuticals, DEC 1, 2018, View Source [SID1234531788]). The clinical results are being presented today in a poster session at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting taking place in San Diego.

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"We continue to see encouraging results from this Phase 2 trial, as X4P-001 drug exposure appears to correlate with increases in absolute neutrophil count and absolute lymphocyte count levels. Increases in these biomarkers are an indication of potential improvement in the pathophysiology underlying WHIM syndrome. An example of clinical improvement and impact on symptoms was the continued reduction in a WHIM patient’s human papillomavirus-related warts following X4P-001 therapy," said David C. Dale, MD, Professor of Medicine at the University of Washington School of Medicine, Seattle, WA, and lead investigator of the trial.

The poster presentation at ASH (Free ASH Whitepaper) describes results from the first 8 patients with genetically confirmed WHIM syndrome and demonstrates the dose-dependent biomarker activity used to support dose selection for the Phase 3 trial. Additional updates on safety and clinical activity across all patients who were enrolled as of the August 17, 2018 data-cut off are also presented in the poster.

Information about the clinical trial of X4P-001 in patients with WHIM syndrome can be found on clinicaltrials.gov: View Source

"X4P-001 in WHIM syndrome is X4’s lead product candidate and our team is rapidly advancing toward the Phase 3 trial, with the goal of delivering X4P-001 to the global community of WHIM patients who currently lack any approved treatment specifically for this disease," said Paula Ragan, PhD, president and chief executive officer of X4 Pharmaceuticals. "We are confident in our path forward based on these favorable Phase 2 results, and we look forward to starting the pivotal Phase 3 trial in the first half of 2019."

About WHIM Syndrome
WHIM syndrome is a primary immunodeficiency disease caused by genetic mutations in the CXCR4 receptor gene resulting in susceptibility to certain types of infections. WHIM is an abbreviation for the characteristic clinical symptoms of the syndrome: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. Within the overall category of primary immunodeficiencies, there are between 15,000 and 100,000 patients in the U.S. who are classified with primary immunodeficiency disease of unknown origin – of which WHIM is one.1,2,3 WHIM syndrome is a rare disorder and the precise prevalence or incidence of patients that have the genetic mutation responsible for WHIM syndrome is unknown. Individuals with WHIM syndrome are more susceptible to potentially life-threatening bacterial infections.4 Additionally, WHIM syndrome is associated with significant morbidity beginning in early childhood and continuing throughout life. Current therapy is limited to treatment of acute infections with antibiotics or prevention of infections through the use of intravenous immunoglobulin or G-CSF. There is no approved therapy for the treatment of WHIM syndrome.

On December 1, 2018 ArQule, Inc. (Nasdaq:ARQL) reported that it will present clinical data on the company’s BTK inhibitor, ARQ 531, in a poster presentation at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition to be held from December 1 to 4, 2018 in San Diego (Press release, ArQule, DEC 1, 2018, View Source [SID1234531787]).

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Updated safety, PK, biomarker and anti-tumor activity data from the company’s Phase 1 dose escalation study in patients with relapsed or refractory hematologic malignancies (ARQ 531-101) will be presented.

Presentation Details

Title:

A Phase 1 Dose Escalation Study of ARQ 531 in Selected Patients with Relapsed or Refractory Hematologic Malignancies

Abstract #: 3136
Session: CLL: Therapy, excluding Transplantation: Poster II
Date: Sunday, December 2, 2018
Time: 6:00-8:00 p.m. PT
Location: San Diego Convention Center, Hall GH

About BTK and ARQ 531
Bruton’s tyrosine kinase, BTK, is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers. ARQ 531 is an orally bioavailable, potent and reversible BTK inhibitor. Biochemical and cellular studies have shown that ARQ 531 inhibits both the wild type and C481S-mutant forms of BTK. The C481S-mutation is a known resistance mechanism for first generation irreversible BTK inhibitors. In preclinical studies, ARQ 531 has demonstrated good oral bioavailability as well as favorable pharmacokinetic, pharmacodynamic and metabolic properties.

On December 1, 2018 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported the presentation of clinical data from two ongoing trials of its investigational Bruton’s tyrosine kinase (BTK) inhibitor, zanubrutinib, in patients with mantle cell lymphoma (MCL) (Press release, BeiGene, DEC 1, 2018, View Source;p=irol-newsArticle&ID=2378923 [SID1234531783]). The presentations were made at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), taking place December 1-4, 2018 in San Diego, CA.

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Results from the pivotal Phase 2 trial of zanubrutinib in Chinese patients with relapsed or refractory (R/R) MCL (ClinicalTrials.gov Identifier: NCT03206970) were featured in an oral presentation, while updated results from the global Phase 1 trial of zanubrutinib in patients with multiple subtypes of B-cell malignancies, including treatment naïve (TN) and R/R MCL (ClinicalTrials.gov Identifier: NCT02343120), were featured in a poster presentation.

"Taken together, we believe that these two studies provide encouraging evidence for the use of zanubrutinib as a potential therapy in patients with MCL," said Jane Huang, M.D., Chief Medical Officer, Hematology, at BeiGene. "The results from 86 patients enrolled in our pivotal Phase 2 study in Chinese patients with R/R MCL presented today at ASH (Free ASH Whitepaper), provide a thorough look into the data included in our first new drug application (NDA) in China for zanubrutinib. Additionally, the results from 48 patients with MCL enrolled in our global Phase 1 study illustrated consistent outcomes for patients studied outside of China. We are excited by the prospect that zanubrutinib may be a differentiated BTK inhibitor with deep, durable responses for patients with MCL and potentially for other B-cell malignancies."

Zanubrutinib was discovered by BeiGene scientists, and is being developed globally as a monotherapy and in combination with other therapies to treat various hematologic malignancies. Zanubrutinib is being studied in several clinical trials as part of a broad development program and was granted Fast Track Designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with Waldenström macroglobulinemia (WM). BeiGene plans to submit an initial NDA to the FDA for zanubrutinib in 2019 or early 2020. The NDAs in China for R/R MCL and R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) have been accepted by the National Medical Products Administration (NMPA, formerly known as CFDA) and the MCL filing has been granted priority review.

"Zanubrutinib was shown to be highly active in Chinese patients with R/R MCL, as evidenced by a high rate of complete responses characterized by PET-based imaging. It was also generally well-tolerated, and we are hopeful of its potential to become a new treatment option for Chinese patients with MCL and potentially other forms of B-cell lymphomas," said Yuqin Song, M.D., Ph.D., Associate Professor of Medical Oncology, Deputy Director of the Lymphoma Department at Peking University Cancer Hospital in China, and presenter of results from the pivotal Phase 2 trial in Chinese patients.

"The outcomes observed in patients treated outside of China are generally consistent with the experiences observed in Chinese patients with R/R MCL. Importantly, the high response rates that were observed appear to extend to patients with both TN and R/R MCL," commented Constantine Tam, M.D., Disease Group Lead for Low Grade Lymphoma and Chronic Lymphocytic Leukemia at Peter MacCallum Cancer Center and Director of Hematology at St. Vincent’s Hospital, Australia, and lead author of the poster presentation of results from the global Phase 1 trial.

Summary of Clinical Results From the Pivotal Phase 2 Trial in China
Oral Presentation Data Included in BeiGene’s NDA in China for Zanubrutinib in MCL

This single arm, open-label, multi-center, pivotal Phase 2 trial of zanubrutinib as a monotherapy in Chinese patients with R/R MCL enrolled 86 patients who had received a median of two prior lines of therapy (1-4). Patients were treated with zanubrutinib, dosed at 160 mg orally twice-daily (BID). The primary endpoint of the trial was overall response rate (ORR) assessed by independent review committee (IRC) using PET-based imaging according to the Lugano Classification 2014.

As of March 27, 2018, 85 patients with R/R MCL were evaluable for efficacy and 65 patients (75.6%) remained on study treatment. The median follow-up time for patients enrolled in the trial was 35.9 weeks (1.1-55.9). Results included:

The ORR by IRC was 83.5 percent (71/85); the complete response (CR) rate was 58.8 percent (50/85) and the partial response (PR) rate was 24.7 percent (21/85);

The 24-week progression-free survival (PFS) was estimated at 82 percent. The median PFS had not yet been reached;

With 24.1 weeks median follow-up (0.1-41.1), the median duration of response (DOR) had not yet been reached and 90 percent of responders were still in response at 24 weeks;

Zanubrutinib tolerability was generally consistent with previous reports in patients with various B-cell malignancies and the majority of adverse events (AEs) were grade 1 or 2 in severity. The most frequent AEs of any attribution were neutrophil count decreased (31.4%), rash (29.1%), upper respiratory tract infection (29.1%), and platelet count decreased (22.1%);

The most frequently reported (in >5 percent of patients) grade 3 or higher AEs were neutrophil count decreased (11.6%) and lung infection (5.8%);

Four patients (4.7%) had treatment emergent adverse events (TEAEs) leading to death (one case each of traffic accident, cerebral hemorrhage, pneumonia, and unknown cause in the setting of infection); and

Among events of special interest for BTK inhibitors, diarrhea was observed in nine patients (10.5%), all grade 1-2. Major hemorrhage was observed in 1 patient (1.2%) with blastoid variant of MCL who had intra-parenchymal CNS bleeding. No cases of atrial fibrillation/flutter were reported in this trial.
Summary of Updated Clinical Results From the Global Phase 1 Trial

This open-label Phase 1 trial of zanubrutinib as a monotherapy in patients with different subtypes of B-cell malignancies, including MCL, is being conducted in Australia, New Zealand, the United States, Italy, and South Korea. As of July 24, 2018, 48 patients with TN (n=9) or R/R (n=39) MCL have been enrolled in the trial and the median follow-up time was 12.7 months (0.7-38.0). Forty-five patients including six with TN and 39 with R/R MCL, were evaluable for efficacy in this analysis, per the Lugano 2014 classification. At the time of the data cutoff, 26 patients remained on study treatment. Updated results included:

The ORR by investigator was 88.9 percent (40/45); the CR rate was 26.7 percent (12/45) and the PR rate was 62.2 percent (28/45). The majority of patients were assessed via CT-scan; PET scans were optional per trial protocol;

The median DOR was 16.2 months and the median PFS for R/R patients was 18.0 months (0.7-30.7);

Zanubrutinib tolerability was generally consistent with previous reports in patients with various B-cell malignancies and the majority of AEs were grade 1 or 2 in severity. The most frequent AEs of any attribution were petechia/purpura/contusion (33.3%), diarrhea (33.3%), upper respiratory tract infection (29.2%), fatigue (25.0%), and constipation (18.8%);

Grade 3-5 AEs occurred in 56.3 percent of patients. Grade 3-5 AEs of any attribution reported in > three patients included anemia (8.3%), major hemorrhage (6.3%), cellulitis (6.3%), myalgia (6.3%), neutropenia (6.3%), pneumonia (6.3%); and thrombocytopenia (6.3%);

Discontinuation due to AEs occurred in 18.8 percent of patients with all but one event (peripheral edema) determined to be unrelated to study drug; and

There were four deaths due to AEs, which were all determined by the investigators to be unrelated to zanubrutinib treatment.
Investor Webcast

Date and Time: Monday, December 3, 2018 at 20:00 PST (Tuesday, December 4 at 12:00 China Standard Time)
Webcast: A live webcast and replay of the event will be available on BeiGene’s investor website, View Source
About Mantle Cell Lymphoma
Lymphoma is a diverse group of malignancies that originates from B-, T- or NK- cells. Mantle cell lymphoma (MCL) is typically an aggressive form of non-Hodgkin lymphoma (NHL) that arises from B-cells originating in the "mantle zone." In 2013, the incidence of lymphoma was 4.2 per 100,000 and the mortality was 2.2 per 100,000 in mainland Chinai, making it the eleventh most common cancer and the tenth leading cause of cancer death.ii In the United States, about 70,800 new cases of NHL were expected in 2014, with MCL representing about six percent (about 4,200 cases) of all new cases of NHL in the United Statesiii. Mantle cell lymphoma usually has a poor prognosis, with a median survival of three to four years, although occasionally patients may have an indolent course.iv Frequently, mantle cell lymphoma is diagnosed at a later stage of disease.

About Zanubrutinib
Zanubrutinib (BGB-3111) is an investigational small molecule inhibitor of Bruton’s tyrosine kinase (BTK) that is currently being evaluated in a broad pivotal clinical program globally as a monotherapy and in combination with other therapies to treat various B-cell malignancies.

Clinical trials of zanubrutinib include a global Phase 1 trial; a fully-enrolled, global Phase 3 clinical trial in patients with Waldenström macroglobulinemia (WM) comparing zanubrutinib to ibrutinib, the currently approved BTK inhibitor for WM; a global Phase 3 clinical trial in patients with previously untreated chronic lymphocytic leukemia (CLL); a pivotal Phase 2 trial in patients with relapsed/refractory (R/R) follicular lymphoma in combination with GAZYVA (obinutuzumab); and a Phase 3 trial comparing zanubrutinib to ibrutinib in patients with R/R CLL/small lymphocytic lymphoma (SLL). In China, BeiGene has completed enrollment in two other pivotal Phase 2 clinical trials of zanubrutinib in patients with CLL/SLL and WM. New drug applications (NDA) for zanubrutinib in patients with R/R MCL and in patients with R/R CLL/SLL have been accepted by the National Medical Products Administration (NMPA, formerly known as CFDA) and the MCL filing has been granted priority review.

On December 1, 2018 Seattle Genetics, Inc. (Nasdaq:SGEN) reported its highlighted data from three ongoing clinical trials evaluating the combination of ADCETRIS (brentuximab vedotin) and Opdivo (nivolumab) at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in San Diego, Calif., December 1-4, 2018 (Press release, Seattle Genetics, DEC 1, 2018, View Source [SID1234531782]). Initial data were presented from a phase 2 clinical trial evaluating the combination in relapsed or refractory primary mediastinal large B-cell lymphoma (PMBL). In addition, data were presented from the ongoing phase 1/2 clinical trial evaluating the combination in relapsed or refractory classical Hodgkin lymphoma (HL). Lastly, an oral presentation on Monday, December 3, 2018 will highlight initial data from a phase 2 study evaluating combination approaches with ADCETRIS, Opdivo and bendamustine in children, adolescents and young adults with relapsed or refractory classical HL. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL that plays a role in tumor growth and survival. Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to harness the body’s own immune system to help restore anti-tumor immune response. ADCETRIS and Opdivo are not approved in combination for the treatment of relapsed or refractory PMBL, HL or for other indications.

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"Our goal with ADCETRIS is to identify the most effective treatment strategies to improve the outcome of patients, and the combination of ADCETRIS and Opdivo has demonstrated enhanced activity with a tolerable safety profile in Hodgkin lymphoma and now a type of non-Hodgkin lymphoma called primary mediastinal large B-cell lymphoma, or PMBL," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. "In the Hodgkin lymphoma setting, ADCETRIS plus Opdivo data continue to support investigation of this combination regimen in multiple ongoing studies. The initial data reported from the phase 2 PMBL clinical trial demonstrate a high level of activity of the combination, with an objective response rate of 70 percent and a complete response rate of 27 percent. We and BMS are exploring specific settings where the combination of ADCETRIS and Opdivo has the potential to improve patient outcomes."

Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Preliminary Results from the Phase 2 Checkmate 436 Trial (Abstract #1691, poster presentation on Saturday, December 1, 2018)

Data from the Checkmate 436 phase 2 trial of 30 patients with relapsed or refractory PMBL who received a combination of ADCETRIS plus Opdivo treatment after failure of frontline therapy or autologous stem cell transplant (ASCT) will be presented for the first time. Patients were treated once every three weeks until disease progression or unacceptable toxicity. The median age of patients was 35.5 years. Key findings will be presented in a poster presentation by Alison Moskowitz, M.D., Clinical Director, Lymphoma Inpatient Unit, Memorial Sloan Kettering Cancer Center, New York, and include:

Of 30 response-evaluable patients, 21 patients (70 percent) had an objective response, including eight patients (27 percent) with a complete response and 13 patients (43 percent) with a partial response, three patients (10 percent) with stable disease, four patients (13 percent) with progressive disease and two patients (seven percent) unable to determine.
Median time to response was 1.3 months and time to complete response was 3 months. Median duration of response and duration of complete response were not reached.
The most common adverse events (AEs) of any grade in at least 20 percent of patients were neutropenia (27 percent) and peripheral neuropathy (20 percent). The most common Grade 3 or 4 AEs were neutropenia (27 percent); thrombocytopenia and decreased neutrophil count (seven percent each); and hypersensitivity, diarrhea and maculopapular rash (all three percent). Immune-mediated AEs included diarrhea, maculopapular rash and hyperthyroidism.
Phase 1/2 Study of Brentuximab Vedotin in Combination with Nivolumab in Patients with Relapsed or Refractory Classic Hodgkin Lymphoma: Part 3 (Concurrent Dosing) Results and Updated Progression-Free Survival Results from Parts 1 and 2 (Staggered Dosing) (Abstract #1635, poster presentation on Saturday, December 1, 2018)

Data will be reported from 30 patients with relapsed or refractory HL who received concurrent combination of ADCETRIS plus Opdivo treatment after failure of frontline therapy, representing Part 3 of the study. Patients were treated once every three weeks, with up to four cycles of combination therapy in the outpatient setting. After completion of the fourth cycle of treatment, patients were eligible to undergo an ASCT. The median age of patients was 31.5 years. Data from Parts 1 and 2 of the study were recently reported at the 11th International Symposium on Hodgkin Lymphoma (ISHL) and can be found here. Key findings will be presented in a poster presentation and include:

Of 30 response-evaluable patients, 28 patients (93 percent) had an objective response, including 24 patients (80 percent) with a complete response and four patients (13 percent) with a partial response, one patient each (three percent) with stable and progressive disease.
After a median follow-up time of 12.7 months, the estimated PFS at 12 months was 89 percent.
The most common AEs of any grade occurring prior to ASCT or subsequent salvage therapy in at least 15 percent of patients were nausea (57 percent), diarrhea and fatigue (37 percent each), vomiting (33 percent), infusion-related reaction (IRR; 30 percent), headache (27 percent), pruritus and pyrexia (23 percent each), and abdominal pain and chills (20 percent each). The majority of IRR AE symptoms were Grade 2 or less and included no treatment discontinuations.
An additional poster will be presented on Monday, December 3, 2018 from the phase 1/2 clinical trial evaluating ADCETRIS in combination with Opdivo in relapsed or refractory HL titled "Baseline Tumor Transcriptome Characteristics Associated with the Response of Relapsed/Refractory Hodgkin Lymphoma Patients to Brentuximab Vedotin in Combination with Nivolumab" (Abstract #2837).

Additional ADCETRIS and Opdivo ASH (Free ASH Whitepaper) Data Presentation

The first data will be reported in an oral presentation from the phase 2 CheckMate-744 study, the first risk-stratified, response-adapted study of ADCETRIS and Opdivo, followed by ADCETRIS and bendamustine for suboptimal response, in children, adolescents and young adults with relapsed/refractory classical HL, prior to ASCT. At time of analysis, all evaluable patients achieved complete metabolic remission after completing induction and, as needed, intensification therapy. The most common AEs were nausea (53 percent), diarrhea (31 percent) and pyrexia (28 percent). No AEs led to discontinuation and there were no deaths. Presentation information includes:

Response-Adapted Therapy with Nivolumab and Brentuximab Vedotin (BV), Followed by BV and Bendamustine for Suboptimal Response, in Children, Adolescents and Young Adults with Standard Risk Relapsed/Refractory Classical Hodgkin Lymphoma (Abstract #927, oral presentation on Monday, December 3, 2018 at 5:00 p.m. PT at the San Diego Convention Center, Room 6F)
About ADCETRIS (brentuximab vedotin)

ADCETRIS is being evaluated broadly in more than 70 clinical trials in CD30-expressing lymphomas. These include three recently completed phase 3 trials: ECHELON-2 in frontline peripheral T-cell lymphomas (also known as mature T-cell lymphoma), ECHELON-1 in previously untreated Hodgkin lymphoma, and ALCANZA in cutaneous T-cell lymphoma. The phase 3 CHECKMATE 812 trial of ADCETRIS in combination with Opdivo (nivolumab) for relapsed/refractory Hodgkin lymphoma is ongoing.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS injection for intravenous infusion has received FDA approval for six indications in adult patients with: (1) previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone, (2) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine, (3) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (4) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (5) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (6) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional approval for post-autologous stem cell transplantation (ASCT) consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression.

ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (2) the treatment of adult patients with relapsed or refractory sALCL, (3) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, and (4) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.

ADCETRIS has received marketing authorization by regulatory authorities in 72 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See select important safety information, including Boxed Warning, below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

On December 1, 2018 ImmunoGen, Inc., (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that new data from the ongoing Phase 1 studies of IMGN632 and IMGN779, next-generation CD123- and CD33-targeting ADCs, respectively, in patients with relapsed or refractory adult acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) will be presented during an oral session at the 60thAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego (Press release, ImmunoGen, DEC 1, 2018, View Source [SID1234531781]). Preclinical data for IMGN632 as a monotherapy in BPDCN patient-derived xenografts, as well as in combination with a PARP inhibitor in AML models, will also be presented at the conference.

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The data presented at ASH (Free ASH Whitepaper) demonstrate the potential of ADCs generated from the company’s IGN platform to overcome the narrow therapeutic window seen with previous generations of DNA-targeted agents and offer new treatment options for AML and other hematological malignancies.

"We designed our IGN payloads to alkylate one strand of DNA to produce potent anti-leukemia activity, while reducing toxicity to normal cells caused by the double-stranded damage associated with earlier DNA-acting approaches," said Anna Berkenblit, MD, Vice President and Chief Medical Officer of ImmunoGen. "IMGN779 and IMGN632 each incorporate an IGN payload and we are pleased to share Phase I clinical results for both programs today at ASH (Free ASH Whitepaper)."

"With IMGN632, we are encouraged by both the tolerability and responses seen thus far, including repeat dosing and complete remissions in AML and BPDCN," said Naval Daver, MD, Associate Professor in the Department of Leukemia at MD Anderson Cancer Center. "We look forward to continuing to enroll patients at several dose levels to establish a recommended Phase 2 dose and schedule for both indications."

"With IMGN779, I am encouraged to see a significant decrease in blasts in many patients with some achieving CRi," said Jorge Cortes, MD, Deputy Chair and Professor of Medicine in the Department of Leukemia at MD Anderson Cancer Center. "The anti-leukemia activity and tolerability seen with both the weekly and the every two week schedule support continued enrollment to identify a dose and schedule to enable further development of IMGN779 as combination therapy in AML."

Phase 1 Data on IMGN632 in AML and BPDCN

Key initial findings from the Phase 1 study of IMGN632 (Abstract #27) include the following:

IMGN632 was administered to 33 patients over dose levels ranging from 0.015 to 0.45 mg/kg intravenously every three weeks. IMGN632 displays a tolerable safety profile and anti-leukemia activity at doses up to 0.3 mg/kg.
Pharmacokinetic (PK) exposures and pharmacodynamic (PD) CD123 saturation increase with dose.
Reported adverse events (AEs) were consistent with underlying disease, with no evidence of cumulative toxicity following multiple doses (up to 6 doses).
Single dose limiting toxicities (DLTs) were seen at the three highest dose levels tested: one prolonged neutropenia and two reversible cases of veno-occlusive disease.
Six of 23 evaluable AML patients (26%) across multiple dose levels achieved an objective response, including two complete remissions (CR) and four CRs with incomplete recovery (CRi) in heavily pretreated patients, including over 60% of patients with primary or relapsed refractory disease.
Two of three evaluable BPDCN patients achieved an objective response after a single dose of IMGN632, 1 CRi and 1 partial remission.
Enrollment in expansion cohorts continues to identify a recommended Phase 2 dose and schedule for both AML and BPDCN.
Phase 1 Data on IMGN779 in AML

Key findings presented from the Phase 1 study of IMGN779 (Abstract #26) include the following:

IMGN779 continues to display a tolerable safety profile with repeat dosing across a wide range of doses explored in 57 patients with relapsed AML. Patients across both schedules (weekly and every two weeks) received a median of four doses of IMGN779 (range, 1-40).
Plasma IMGN779 concentrations indicate consistent and sustained exposure through seven days at doses ≥0.39 mg/kg; the weekly schedule provides more consistent pharmacodynamic CD33 saturation.
Reported AEs were consistent with underlying disease, and with no evidence of cumulative toxicity following multiple doses (up to 40 doses).
One DLT of veno-occlusive disease was observed at the highest dose tested on the weekly schedule, 1.2 mg/kg.
Anti-leukemia activity was seen at doses ≥0.39 mg/kg in both schedules:
41% (12 of 29) of evaluable patients showed a >30% reduction in bone marrow blasts with eight patients (28%) having <8% residual blasts, and two having a CR or CRi.
Enrollment continues to identify the recommended Phase 2 dose and schedule.
Oral Presentation Details

Title: Maturing Clinical Profile of IMGN779, a Next-Generation CD33-Targeting Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Acute Myeloid Leukemia
Presenter:Jorge Cortes, MD Anderson Cancer Center
Day/Time:Saturday, December 1, 2018, 7:45am PST (Oral session 613)
Location: Manchester Grand Hyatt San Diego, Seaport Ballroom F
Abstract: 26
Title: A Phase I, First-in-Human Study Evaluating the Safety and Preliminary Antileukemia Activity of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate, in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Other CD123-Positive Hematologic Malignancies
Presenter: Naval Daver, MD Anderson Cancer Center
Senior Author: Hagop Kantarjian, MD Anderson Cancer Center
Day/Time: Saturday, December 1, 2018, 8:00am PST (Oral session 613)
Location: Manchester Grand Hyatt San Diego, Seaport Ballroom F
Abstract: 27
Preclinical Poster Presentations on IMGN632 in AML and BPDCN

Preclinical data on anti-leukemia activity for IMGN632 in combination with a PARP inhibitor in AML, as well as a monotherapy in BPDCN will also be presented.

Poster Presentation Details

Title: Synergistic anti-leukemia activity of PARP inhibition combined with IMGN632, an anti-CD123 antibody-drug conjugate in acute myeloid leukemia models
Day/Time: Sunday, December 2, 2018, 6:00-8:00pm PST (Poster session 604)
Senior author: Eunice Wang, Roswell Park Cancer Institute
Abstract: 2647
Title: Pre-clinical efficacy of CD123-targeting antibody-drug conjugate IMGN632 in Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) models
Day/Time: Monday, December 3, 2018, 6:00-8:00pm PST (Poster session 605)
Senior author:Marina Konopleva, MD Anderson Cancer Center
Abstract: 3956
Additional information can be found at www.hematology.org, including abstracts.

About IMGN779

IMGN779 is a novel ADC that combines a high-affinity, humanized anti-CD33 antibody, a cleavable disulfide linker, and one of ImmunoGen’s novel indolino-benzodiazepine payloads, called IGNs, which alkylate DNA without crosslinking, resulting in potent preclinical anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.1,2 IMGN779 is in Phase 1 clinical testing for the treatment of AML.

About IMGN632

IMGN632 is a novel, anti-CD123 antibody-drug conjugate that is a potential treatment for AML, BPDCN, and other CD123-positive malignancies. IMGN632 uses a novel humanized anti-CD123 antibody coupled via a peptide linker to a unique DNA-alkylating IGN payload. In preclinical models, IMGN632 has exhibited potent antitumor activity with a wide therapeutic index in AML, BPDCN, and acute lymphoblastic leukemia (ALL). IMGN632 is in Phase 1 clinical testing for the treatment of AML and BPDCN.

About IGNs

Indolino-benzodiazepine cancer-killing agents, or IGNs, are a new class of cancer-killing agent developed by ImmunoGen for use in ADCs. These ultra-potent, DNA-acting IGNs alkylate DNA without crosslinking, which preclinically has resulted in potent anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.3.4 IMGN779, a CD33-targeting ADC in Phase 1 testing for AML, was the first IGN ADC to enter clinical testing. IMGN632, a CD123-targeting ADC entering Phase 1 testing for AML and BPDCN, deploys a novel IGN payload.

About Acute Myeloid Leukemia (AML)

AML is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems, and anemia.

It is estimated that, in the U.S. alone, 21,380 patients will be diagnosed with AML this year and 10,590 patients will die from the disease.5